PIEZO2 in sensory neurons and urothelial cells coordinates urination.

Henry Miller stated that "to relieve a full bladder is one of the great human joys". Urination is critically important in health and ailments of the lower urinary tract cause high pathological burden. Although there have been advances in understanding the central circuitry in the brain that facilitates urination1-3, there is a lack of in-depth mechanistic insight into the process. In addition to central control, micturition reflexes that govern urination are all initiated by peripheral mechanical stimuli such as bladder stretch and urethral flow4. The mechanotransduction molecules and cell types that function as the primary stretch and pressure detectors in the urinary tract mostly remain unknown. Here we identify expression of the mechanosensitive ion channel PIEZO2 in lower urinary tract tissues, where it is required for low-threshold bladder-stretch sensing and urethral micturition reflexes. We show that PIEZO2 acts as a sensor in both the bladder urothelium and innervating sensory neurons. Humans and mice lacking functional PIEZO2 have impaired bladder control, and humans lacking functional PIEZO2 report deficient bladder-filling sensation. This study identifies PIEZO2 as a key mechanosensor in urinary function. These findings set the foundation for future work to identify the interactions between urothelial cells and sensory neurons that control urination.

Functional nitrergic innervation of smooth muscle structures in the mucosa of pig lower urinary tract.

Neurally released nitric oxide (NO) functions as an inhibitory neurotransmitter of urethral but not detrusor smooth muscles while relaxing bladder vasculature and muscularis mucosae (MM). Here, the distribution of nitrergic nerves was examined in the mucosa of pig lower urinary tract using immunohistochemistry, and their vasodilatory functions were studied by measuring arteriolar diameter changes. Properties of smooth muscle cells in the lamina propria (SMC-LP) of urethra and trigone were also investigated using florescence Ca2+ imaging. In the bladder mucosa, neuronal nitric oxide synthase (nNOS)-immunoreactive nitrergic fibres projected to suburothelial arterioles and venules. Perivascular nitrergic nerves were intermingled with but distinct from tyrosine hydroxylase (TH)-immunoreactive sympathetic or calcitonin gene-related peptide (CGRP)-immunoreactive afferent nerves. MM receive a nitrergic but not sympathetic or afferent innervation. In the mucosa of urethra and trigone, nitrergic nerves were in close apposition with sympathetic or afferent nerves around suburothelial vasculature but did not project to SMC-LP. In suburothelial arterioles of bladder and urethra, N ω-nitro-L-arginine (L-NA, 100 µM), an NOS inhibitor, enhanced electrical field stimulation (EFS)-induced sympathetic vasoconstrictions, while tadalafil (10 nM), a phosphodiesterase type 5 (PDE5) inhibitor, suppressed the vasoconstrictions. SMC-LP developed asynchronous spontaneous Ca2+ transients without responding to EFS. The spontaneous Ca2+ transients were enhanced by acetylcholine (1 µM) and diminished by noradrenaline (1 µM) but not SIN-1 (10 µM), an NO donor. In the lower urinary tract mucosa, perivascular nitrergic nerves appear to counteract the sympathetic vasoconstriction to maintain the mucosal circulation. Bladder MM but not SMC-LP receive an inhibitory nitrergic innervation.

Neurophysiological control of urinary bladder storage and voiding-functional changes through development and pathology.

The effective storage of urine and its expulsion relies upon the coordinated activity of parasympathetic, sympathetic, and somatic innervations to the lower urinary tract (LUT). At birth, all mammalian neonates lack the ability to voluntary regulate bladder storage or voiding. The ability to control urinary bladder activity is established as connections to the central nervous system (CNS) form through development. The neural regulation of the LUT has been predominantly investigated in adult animal models where comparatively less is known about the neonatal and postnatal neurophysiological development that facilitate urinary continence. Furthermore, congenital neurological or anatomical defects can adversely affect both storage and voiding functions through postnatal development and into adulthood, leading to secondary conditions including vesicoureteral reflux, chronic urinary tract infections, and end-stage renal disease. Therefore, the aim of the review is to provide the current knowledge available on neurophysiological regulation of the LUT through pre- to postnatal development of human and animal models and the consequences of congenital anomalies that can affect LUT neural function.

The Effect of Castration on Peripheral Autonomic Neurons Supplying Mammalian Male Genitourinary System.

This review paper deals with the influence of androgens (testosterone) on pelvic autonomic pathways in male mammals. The vast majority of the relevant information has been gained in experiments involving castration (testosterone deprivation) performed in male rats, and recently, in male pigs. In both species, testosterone significantly affects the biology of the pathway components, including the pelvic neurons. However, there are great differences between rats and pigs in this respect. The most significant alteration is that testosterone deprivation accomplished a few days after birth results some months later in the excessive loss (approximately 90%) of pelvic and urinary bladder trigone intramural neurons in the male pig, while no changes in the number of pelvic neurons are observed in male rats (rats do not have the intramural ganglia). In the castrated pigs, much greater numbers of pelvic neurons than in the non-castrated animals express CGRP, GAL, VIP (peptides known to have neuroprotective properties), and caspase 3, suggesting that neurons die due to apoptosis triggered by androgen deprivation. In contrast, only some morpho-electrophysiological changes affecting neurons following castration are found in male rats. Certain clinicopathological consequences of testosterone deprivation for the functioning of urogenital organs are also discussed.

5-HT3 Signaling Alters Development of Sacral Neural Crest Derivatives That Innervate the Lower Urinary Tract.

The autonomic nervous system derives from the neural crest (NC) and supplies motor innervation to the smooth muscle of visceral organs, including the lower urinary tract (LUT). During fetal development, sacral NC cells colonize the urogenital sinus to form pelvic ganglia (PG) flanking the bladder neck. The coordinated activity of PG neurons is required for normal urination; however, little is known about the development of PG neuronal diversity. To discover candidate genes involved in PG neurogenesis, the transcriptome profiling of sacral NC and developing PG was performed, and we identified the enrichment of the type 3 serotonin receptor (5-HT3, encoded by Htr3a and Htr3b). We determined that Htr3a is one of the first serotonin receptor genes that is up-regulated in sacral NC progenitors and is maintained in differentiating PG neurons. In vitro cultures showed that the disruption of 5-HT3 signaling alters the differentiation outcomes of sacral NC cells, while the stimulation of 5-HT3 in explanted fetal pelvic ganglia severely diminished neurite arbor outgrowth. Overall, this study provides a valuable resource for the analysis of signaling pathways in PG development, identifies 5-HT3 as a novel regulator of NC lineage diversification and neuronal maturation in the peripheral nervous system, and indicates that the perturbation of 5-HT3 signaling in gestation has the potential to alter bladder function later in life.

Adreno-muscarinic synergy in the male human urinary outflow tract.

AIM: To examine putative interaction between adrenergic and muscarinic contractile activation in the human urinary outflow tract. METHODS: Tissue from the trigone and prostatic urethra was obtained from 12 cystectomy and 16 prostatectomy specimen. Contractions were elicited by exposure to exogenous agonists before and after inhibition of Rho kinase and protein kinase c (PKC). Immunofluorescence and Western-blot studies were performed using antibodies to muscarinic M3-receptors (M3-R) and alpha1A-adrenoreceptors (alpha1A-AR). The study is registered with ClinicalTrials.gov, number NCT01227447. RESULTS: There was strong co-localization of M3-R and alpha1A-AR on trigonal and urethral myocytes. Western blot analysis revealed a significantly higher expression of alpha1A-AR in the superficial than in the deep trigone. Phenylephrine (PE, 1 µm) augmented contractions induced by carbachol (CA, 3 µm) to more than threefold control in the male superficial trigone, and to about sevenfold control in the proximal urethra. No such potentiation could be detected in female bladder outlet. Both PKC inhibitor GF 109203X and Rho kinase inhibitor Y-27632 reduced responses to 1 µM PE as well as to 3 µM CA significantly. However, the synergistic effect of the combined intervention remained proportionally unaffected. CONCLUSIONS: Muscarinic and adrenergic receptor activation exerts a strong synergistic effect in the male human bladder trigone and proximal urethra.

Voiding Dysfunction After Non-urologic Pelvic Surgery.

PURPOSE OF REVIEW: Urinary dysfunction is a common entity in patients undergoing radical pelvic surgery for non-urologic malignancies. These dysfunctions may manifest as lower urinary tract symptoms (LUTS) or signs such as urinary retention or leakage. Review of current literature is performed to describe the differing urinary dysfunctions that manifest after colorectal resection, hysterectomy, and sacrectomy. RECENT FINDINGS: Conventional radical surgery for pelvic malignancies often will result in debilitating functional problems. As advances in surgical techniques and management options become more available, patients can have better functional outcomes, specifically in the lower urinary tract. Nerve-sparing techniques as well as vascular preservation are becoming more important to preserve function as patient survival is improving. Additionally, newer methods are being explored, such as nerve stimulation for those who are unable to empty adequately. This article also addresses different management options for specific voiding dysfunction that may result from pelvic surgery. Preventative strategies such as nerve preservation during surgery are an important concept to prevent urinary dysfunction. The goal to good functional outcomes includes maintaining reservoir compliance and capacity as well as allowing proper outlet for voiding. We discuss different modalities to help achieve a functional lower urinary tract for patients with lower urinary tract dysfunction after pelvic surgery.

Laboratory practical to study the differential innervation pathways of urinary tract smooth muscle.

In the mammalian lower urinary tract, there is a reciprocal relationship between the contractile state of the bladder and urethra. As the bladder fills with urine, it remains relaxed to accommodate increases in volume, while the urethra remains contracted to prevent leakage of urine from the bladder to the exterior. Disruptions to the normal contractile state of the bladder and urethra can lead to abnormal micturition patterns and urinary incontinence. While both the bladder and urethra are smooth-muscle organs, they are differentially contracted by input from cholinergic and sympathetic nerves, respectively. The laboratory practical described here provides an experiential approach to understanding the anatomy of the lower urinary tract. Several key factors in urinary tract physiology are outlined, e.g., the bladder is contracted by activation of the parasympathetic pathway via cholinergic stimulation on muscarinic receptors, whereas the urethra is contracted by activation of the sympathetic pathway via adrenergic stimulation on α1-adrenoceptors. This is achieved by measuring the force generated by bladder and urethra smooth muscle to demonstrate that acetylcholine contracts the smooth muscle of the bladder, whereas adrenergic agonists contract the urethral smooth muscle. An inhibition of these effects is also demonstrated by application of the muscarinic receptor antagonist atropine and the α1-adrenergic receptor blocker phentolamine. A list of suggested techniques and exam questions to evaluate student understanding on this topic is also provided.

Undiagnosed neurological disease as a potential cause of male lower urinary tract symptoms.

PURPOSE OF REVIEW: In the central nervous system there are many regulatory processes controlling the lower urinary tract. This review considers the possibility that urinary dysfunction may precede diagnosis of neurological disease. RECENT FINDINGS: Lower urinary tract symptoms (LUTS) occur early in multiple system atrophy, Parkinson's disease and normal pressure hydrocephalus, and may present before neurological diagnosis. Some people present with LUTS and subsequently are diagnosed with multiple sclerosis or a spinal condition. In male LUTS, the symptoms could reflect early stages of a neurological disease, which has not yet been diagnosed ('occult neurology'). Key symptoms include erectile dysfunction, retrograde ejaculation, enuresis, loss of filling sensation or unexplained stress urinary incontinence. Directed questioning should enquire about visual symptoms, back pain, anosmia, bowel dysfunction and incontinence, or memory loss. Examination features can include resting tremor, 'croaky' speech, abnormal gait, orthostatic hypotension, ataxia, or altered perineal sensation. Imaging, such as MRI scan, should only be requested after expert neurological examination, to ensure the correct parts of the central nervous system are scanned with appropriate radiological protocols. SUMMARY: Urologists should consider an undiagnosed neurological condition can be present in a few cases. Any finding should be further evaluated by colleagues with relevant expertise.

Postoperative phosphodiesterase type 5 inhibitor administration increases the rate of urinary continence recovery after bilateral nerve-sparing radical prostatectomy.

OBJECTIVES: To investigate the effect of phosphodiesterase type 5 inhibitor on urinary continence recovery after bilateral nerve-sparing radical prostatectomy. METHODS: We analyzed data of 393 open bilateral nerve-sparing radical prostatectomies carried out between 2005 and 2010. Patients who recovered urinary continence within the first month after catheter removal (n = 52) were excluded. This resulted in 341 evaluable patients. Urinary continence recovery was defined as being completely pad free over a period of 24 h. Patients were stratified according to postoperative daily (n = 58; 17%), on-demand (n = 112; 32.8%) and no (n = 171; 50.1%) phosphodiesterase type 5 inhibitor use. The effect of phosphodiesterase type 5 inhibitor use on urinary continence was assessed using the Kaplan-Meier method. Uni- and multivariable Cox regression analyses were used to test the association between phosphodiesterase type 5 inhibitor and urinary continence recovery after adjusting for cofounders. RESULTS: At a mean follow up of 36.4 months after surgery (median: 33), 288 patients (84.5%) recovered urinary continence after bilateral nerve-sparing radical prostatectomy. Patients who did not use phosphodiesterase type 5 inhibitor after surgery had lower rates of urinary continence recovery at 1- and 2-year follow up as compared with patients taking phosphodiesterase type 5 inhibitor (67.1 vs 86.7% and 76 vs 94.4%, respectively; P < 0.001). After adjusting for all confounders, multivariable analysis showed that phosphodiesterase type 5 inhibitor use, either on demand or daily, had a positive impact on urinary continence recovery (P = 0.03). CONCLUSIONS: Patients taking phosphodiesterase type 5 inhibitor have higher urinary continence recovery rates as compared with patients left untreated after bilateral nerve-sparing radical prostatectomy. An improvement in sphincteric and pelvic floor blood supply might be responsible for this beneficial effect associated with the use of phosphodiesterase type 5 inhibitor.

Urinary retention for the neurologist.

Urinary retention is a common problem, most often due to an anatomical lesion in the urinary tract causing obstruction, such as a urethral stricture or prostate enlargement. However, a subset of patients have no structural urological lesion, and so require neurological evaluation. We present a patient with acute urinary retention who was found to have chronic meningitis, and review the neurological causes for urinary retention.

Can we identify men who will have complications from benign prostatic obstruction (BPO)? ICI-RS 2011.

AIMS: This ICI-RS report aims to analyze morphological or functional complications of the lower or upper urinary tract in elderly men, clarify the association between complications and benign prostatic obstruction (BPO) and define men who will develop these complications. Research proposals to further enlighten these associations were to be defined. METHODS: A think-tank discussion was held on the annual ICI-RS meeting in 2011. The published literature between 1966 and 2011 was reviewed and research proposals were defined with all congress participants. RESULTS: Post-void residual, bladder diverticula or calculi, vesico-ureteral reflux, hydronephrosis, renal insufficiency, and urinary retention appear with greater prevalence in patients with symptoms or signs of benign prostatic hyperplasia. BPO may directly or indirectly be responsible for these complications but conclusive evidence for BPO as the primary cause does not exist. Many of the complications have a multifactorial etiology and BPO is only partially responsible. It is currently impossible to define men who will develop complications. CONCLUSIONS: In contrast to the widespread belief of urologist, there is only rudimentary data available showing no convincing association between urinary tract complications and BPO. The ICI-RS proposes that prospective trials are conducted to demonstrate the association between complications and BPO by using cystometry, pressure-flow (P/F) studies, and other commonly used BPO parameters in men with complications and comparing those with a cohort of age-matched men without complications. Non-invasive proxy parameters of BPO, for example, ultrasonic measurement of detrusor wall thickness, can be used instead of P/F studies especially in longitudinal trials.

Individualized radical hysterectomy procedure using intraoperative electrical stimulation for patients with cervical cancer.

OBJECTIVE: In this study, by monitoring the varied distributions of nerve fascicles using intraoperative electrical stimulation (IES), we sought to establish an individualized operation based on the patient's unique nerve distribution pattern, and to determine whether this technique would result in a higher preservation rate. MATERIALS/METHODS: Radical hysterectomy was performed from 2002 to 2010. Patients in group A are the 48 cases from 2002 to 2007 in which nerve-sparing radical hysterectomy using IES as our previous report was performed. Patients in group B are the 38 cases from 2008 to 2010 in which we used our new method, which was individualized to each patient. Urodynamic study (UDS) was used to confirm nerve preservation. Nerve preservation was defined as confirming distinct detrusor contraction during urinary voiding. RESULTS: In group B, nerve preservation rate was higher than in group A (75% vs 9 0%, P = 0.067). We classified the case-by-case nerve anatomy as whether the nerve fascicle was mainly on the medial side or on the lateral side of the deep uterine vein. The lateral type anatomy was observed unilaterally in 6 cases and bilaterally in 1 case. In summary, the lateral type anatomy was observed in 8 (29%) of 28 sides. In the cases evaluated by UDS, the positive predictive value of IES was 95% in group A and 100% in group B. CONCLUSIONS: Our method of IES showed a high positive predictive value of nerve preservation as confirmed by UDS. By delineating the nerve tract in detail using IES, it is possible to individualize the operation based on each patient's anatomy, with an improved nerve preservation rate.

Neurophysiology and therapeutic receptor targets for stress urinary incontinence.

Stress urinary incontinence is the most common type of urinary incontinence in women. Stress urinary incontinence involves involuntary leakage of urine in response to abdominal pressure caused by activities, such as sneezing and coughing. The condition affects millions of women worldwide, causing physical discomfort as well as social distress and even social isolation. This type of incontinence is often seen in women after middle age and it can be caused by impaired closure mechanisms of the urethra as a result of a weak pelvic floor or poorly supported urethral sphincter (urethral hypermobility) and/or a damaged urethral sphincter system (intrinsic sphincter deficiency). Until recently, stress urinary incontinence has been approached by clinicians as a purely anatomic problem as a result of urethral hypermobility requiring behavioral or surgical therapy. However, intrinsic sphincter deficiency has been reported to be more significantly associated with stress urinary incontinence than urethral hypermobility. Extensive basic and clinical research has enhanced our understanding of the complex neural circuitry regulating normal function of the lower urinary tract, as well as the pathophysiological mechanisms that might underlie the development of stress urinary incontinence and lead to the development of potential novel strategies for pharmacotherapy of stress urinary incontinence. Therapeutic targets include adrenergic and serotonergic receptors in the spinal cord, and adrenergic receptors at the urethral sphincter, which can enhance urethral reflex activity during stress conditions and increase baseline urethral pressure, respectively. This article therefore reviews the recent advances in stress urinary incontinence research and discusses the neurophysiology of urethral continence reflexes, the etiology of stress urinary incontinence and potential targets for pharmacotherapy of stress urinary incontinence.

Current state of nerve stimulation technique for lower urinary tract dysfunction in children.

PURPOSE: A variety of electrical nerve stimulation methods has been used through the years to treat lower urinary tract dysfunction. Relevant literature was reviewed to analyze techniques and available biomedical devices, technique applicability, indications and usefulness in pediatrics. MATERIALS AND METHODS: An extensive search was performed on PubMed® and MEDLINE® for scientific publications on intravesical, transcutaneous, sacral spine and root, and tibial nerve stimulation in children with lower urinary tract dysfunction of nonneurogenic and neurogenic origin. Relevant articles and controlled studies in adult patients were also considered. The search covered the period 1990 to 2009 and we found approximately 400 articles, of which 29 related to pediatrics. RESULTS: Due to feasibility problems with placebo studies the majority of the studies were noncontrolled, some of them clinical trials on acute urodynamic changes during electrical stimulation or experimental research in animals. Overall only a few randomized trials were found. Regarding types of electrostimulation and indications in children the recent literature emphasizes stimulation far from the anal-genital region, such as sacral transcutaneous electrical nerve stimulation, mainly for refractory overactive bladder. Intravesical stimulation is the procedure of choice to enhance sensation in patients with incomplete neurogenic lesions. Percutaneous tibial nerve stimulation is tolerated by children but has been poorly studied. Sacral neuromodulation using implanted devices remains questionable and needs further clarification of its indications. Magnetic stimulation has rarely been used in children to date. More experimental studies are needed to assess the method of action and refine the parameters of stimulation. CONCLUSIONS: Clinical controlled trials vs sham devices and predictable variables for successful response are urgently needed to address an apparently renewed focus on the use of nerve stimulation in the treatment of pediatric lower urinary tract symptoms.

Electrical stimulation for lower urinary tract dysfunction in children: a systematic review of the literature.

AIMS: To review studies using electrical neural stimulation (ENS), to treat children with non-neurogenic lower urinary tract dysfunctions (LUTD), and to establish the efficacy of this treatment. METHODS: This review was based on an electronic search of the MEDLINE database and the Cochrane Central Search library, from January 1990 to March 2010. INCLUSION CRITERIA: (1) participants aged 0-17 years, (2) participants with a diagnosis of LUTD not related to congenital abnormalities or neurological disease, (3) English language, and (4) treatment by ENS. RESULTS: Seventeen papers were evaluated. Type of ENS varied among studies: sacral transcutaneous ENS in seven, sacral implanted device in four, posterior tibial percutaneous in three, and anogenital, endoanal, and intravesical in one each. There were two randomized clinical trials. Clarity regarding the LUTD being treated was variable. The populations studied were not homogeneous. The duration of treatment and the number of sessions a week were variable among the studies. Electrical parameters used also varied. A range of subjective and objective measures was used to measure treatment success. Rates of complete resolution of the symptoms of OAB, urgency, and daytime incontinence ranged from 31% to 86% [Trsinar and Kraij, Neurourol Urodyn 15: 133-42, 1996; Hagstroem et al., J Urol 182: 2072-8, 2009], 25% to 84% [Hoebeke et al., J Urol 168: 2605-8, 2002; Lordêlo et al., J Urol 182: 2900-4, 2009], 13% to 84% [Malm-Buatsi et al., Urology 70: 980-3, 2007; Lordêlo et al., J Urol 184: 683-9, 2010], respectively. For sacral transcutaneous ENS recurrence ranged from 10% to 25%. Apart from the sacral implantation studies, any reported side effects were mild and transitory. CONCLUSIONS: The literature in the area of interest is sparse. Parasacral TENS has been shown to be more effective than sham in randomized trials in treating OAB. This deserves further research to elucidate the optimal parameters and the children for whom it is most useful.

How does neuromodulation work.

Although sacral neuromodulation (SNM) is approved and successfully used for different urological and proctologic functional diseases for the long-term treatment, less is known about the working mechanisms underlying SNM. This review highlights SNM clinical application, the current data of LUT neuroanatomy and neurophysiology, SNM techniques and its prospective working mechanisms. Functional imaging techniques have facilitated a more detailed insight into the neural network between the central nervous system (CNS) and the lower urinary tract (LUT). In addition to the well-known factors of the spinal micturition pathway, several pontine (e.g. pontine micturition centre) and suprapontine (e.g. cingulate cortex) regions and their interactions have been identified. An attribution of CNS activity levels to different LUT conditions is possible for the first time. Based on this information, different SNM actions could also have been allocated to different ascending/descending pathways and supraspinal regions, whereas acute SNM especially affects regions of learning activity, chronic SNM might result in CNS plasticity even though clinical effectiveness fades after SNM deactivation. Studies to treat fecal incontinence or to prevent detrusor overactivity in complete spinal cord injured patients support the importance of sympathetic pathways for the action of SNM. Despite increasing knowledge about SNM influence on the CNS, the complexity of its underlying working mechanisms is not understood at all. Further investigations with improved functional imaging techniques will enhance our SNM background.

Overview on the lower urinary tract.

This chapter overviews our current knowledge on the subject of the urinary tract, whose fundamental role is to transport urine from the kidneys and then store it at low pressure in the lower urinary tract until it can be voided at a socially convenient time. Current understanding of lower urinary tract function and dysfunction is summarized, with reference to anatomy, innervation, and function. The importance of the neurological system in the normal function of the lower urinary tract is emphasized, with a brief overview of the consequence of neural injury at different levels within the central nervous system. The role of urodynamics in the evaluation of lower urinary tract symptoms is discussed with particular reference to the currently recommended terminology advocated by the International Continence Society and The International Urogynaecological Association.

Neurophysiology of the lower urinary tract.

The lower urinary tract (LUT) has two functions: (1) the storage of waste products in the form of urine and (2) the elimination of those wastes through micturition. The LUT operates in a simple "on-off" fashion, either storing urine or releasing it during voiding. While this activity may seem simple, micturition is controlled by a complex set of peripheral neurons that are, in turn, coordinated by cell groups in the spinal cord, brainstem, and brain. When this careful coordination is interrupted, the control of the bladder is lost, resulting in incontinence or retention of urine. The purpose of this chapter is to review how the neural systems coordinating the activity of the lower urinary tract form neural circuits that are responsible for either maintaining continence (the storage reflex) or inducing micturition (the voiding reflex). We will also discuss the brain centers that enable higher organisms to voluntarily choose the time and place for voiding. Finally, we will discuss how defects in the pathways controlling micturition can lead to urinary incontinence and which treatments may normalize LUT function.

Neuropeptides in lower urinary tract function.

Numerous neuropeptide/receptor systems including vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, calcitonin gene-related peptide, substance P, neurokinin A, bradykinin, and endothelin-1 are expressed in the lower urinary tract (LUT) in both neural and nonneural (e.g., urothelium) components. LUT neuropeptide immunoreactivity is present in afferent and autonomic efferent neurons innervating the bladder and urethra and in the urothelium of the urinary bladder. Neuropeptides have tissue-specific distributions and functions in the LUT and exhibit neuroplastic changes in expression and function with LUT dysfunction following neural injury, inflammation, and disease. LUT dysfunction with abnormal voiding, including urinary urgency, increased voiding frequency, nocturia, urinary incontinence, and pain, may reflect a change in the balance of neuropeptides in bladder reflex pathways. LUT neuropeptide/receptor systems may represent potential targets for therapeutic intervention.